1. Field of the Invention
The present invention relates to the use of compounds which have specific or selective agonist like activity on RARxcex1 retinoid receptors for treatment of diseases and conditions which respond to treatment by such retinoids. More particularly the present invention is directed to the use of RARxcex1 receptor specific or selective agents for the treatment of tumors.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
U.S. Pat. No. 4,740,519 (Shroot et al.), U.S. Pat. No. 4,826,969 (Maignan et al.), U.S. Pat. No. 4,326,055 (Loeliger et al.), U.S. Pat. No. 5,130,335 (Chandraratna et al.), U.S. Pat. No. 5,037,825 (Klaus et al.), U.S. Pat. No. 5,231,113 (Chandraratna et al.), U.S. Pat. No. 5,324,840 (Chandraratna), U.S. Pat. No. 5,344,959 (Chandraratna), U.S. Pat. No. 5,130,335 (Chandraratna et al.), Published European Patent Application Nos. 0 170 105 (Shudo), 0 176 034 A (Wuest et al.), 0 350 846 A (Klaus et al.), 0 176 032 A (Frickel et al.), 0 176 033 A (Frickel et al.), 0 253 302 A (Klaus et al.), 0 303 915 A (Bryce et al.), UK Patent Application GB 2190378 A (Klaus et al.), German Patent Application Nos. DE 3715955 A1 (Klaus et al.), DE 3602473 A1 (Wuest et al., and the articles J. Amer. Acad. Derm. 15: 756-764 (1986) (Sporn et al.), Chem. Pharm. Bull. 33: 404-407 (1985) (Shudo et al.), J. Med Chem. 1988 31, 2182-2192 (Kagechika et al.), Chemistry and Biology of Synthetic Retinoids CRC Press Inc. 1990 p 334-335, 354 (Dawson et al.), describe or relate to compounds which include a tetrahydronaphthyl moiety and have retinoid-like or related biological activity.
U.S. Pat. Nos. 4,980,369, 5,006,550, 5,015,658, 5,045,551, 5,089,509, 5,134,159, 5,162,546, 5,234,926, 5,248,777, 5,264,578, 5,272,156, 5,278,318, 5,324,744, 5,346,895, 5,346,915, 5,348,972, 5,348,975, 5,380,877, 5,399,561, 5,407,937, (assigned to the same assignee as the present application) and patents and publications cited therein, describe or relate to chroman, thiochroman and 1,2,3,4-tetrahydroquinoline derivatives which have retinoid-like biological activity.
U.S. Pat. No. 4,723,028 (Shudo), Published European Patent Application Nos. 0 170 105 (Shudo), German Patent Application No. DE 3524199 A1 (Shudo), PCT WO 91/16051 (Spada et al.), PCT WO 85/04652 (Polus) and J. Med Chem. 1988 31, 2182-2192 (Kagechika et al.), describe or relate to aryl and heteroaryl or diaryl substituted olephines or amides having retinoid-like or related biological activity.
U.S. Pat. Nos. 4,992,468, 5,013,744, 5,068,252, 5,175,185, 5,202,471, 5,264,456, 5,324,840, 5,326,898, 5,349,105, 5,391,753, 5,414,007 and 5,434,173 (assigned to the same assignee as the present application) and patents and publications cited therein, describe or relate to compounds which have retinoid-like biological activity and a structure wherein a phenyl and a heteroaryl or a phenyl and a second phenyl group is linked with an olephinic or acetylenic linkage. Still further, several co-pending applications and recently issued patents which are assigned to the assignee of the present application, are directed to further compounds having retinoid-like activity.
It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARxcex1, RARxcex2 and RARxcex93, in RXR the subtypes are: RXRxcex1, RXBxcex2 and RXRxcex93. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms.
It is also known in the art that the use of retinoid-like compounds for the treatment of various diseases and conditions is not without problems or side effects. The side effects at therapeutic dose levels include headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dislipidemias, skin irritation, headache, hepatotoxicity, etc. These side effects limit the acceptability and utility of retinoids for treating disease. Research is still ongoing in the art to determine which of the RAR or RXR familes and within each family, which of the subtype or subtypes are responsible for mediating certain therapeutic effects, and which type or subtypes are responsible for mediating one or more of the undesired side effects. Accordingly, among compounds capable of binding to retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property. Such selectivity or specificity is useful as a research tool for discovering the roles of the several receptor types and subtypes in mediating the various effects of retinoids in biological systems, and also as aid for designing retinoid drugs with specific therapeutic effects and/or with reduced side effects and toxicity. Along these lines, U.S. Pat. No. 5,324,840 describes a class of compounds in which retinoid-like activity is accompanied by reduced skin toxicity and reduced teratogenic effects. U.S. Pat. No. 5,399,586 describes the use of compounds having RXR retinoid receptor agonist activity for the treatment of mammals afflicted with tumors. U.S. Pat. No. 5,455,265 describes methods of treatment of mammals with compounds having agonist-like activity on RXR receptors. Published PCT application No. WO93/11755 is also directed to the use of compounds which are selective RXR receptor agonists.
The present invention provides methods of treatment of tumors with compounds which are specific or selective to RARxcex1 receptors.
It has been discovered in accordance with the present invention that retinoid-like compounds which act selectively, or preferably even specifically on RARxcex1 receptor subtypes in preference over RARxcex2 and RARxcex93 receptor subtypes, possess desirable pharmaceutical properties associated with retinoids, and are particularly suitable for treatment of tumors, such as acute monocytic leukemia, cervical carcinoma, myeloma, ovarian carcinomas and head and neck carcinomas, without having one or more undesirable side effects of retinoids, such as inducement of weight loss, mucocutaneous toxicity, skin irritation and teratogenecity.
Accordingly, the present invention relates to the use of RARxcex1 specific or selective retinoid compounds for the treatment of diseases and conditions which respond to treatment by such compounds, and particularly to the treatment of tumors, primarily acute monocytic leukemia, cervical carcinoma, myeloma, ovarian carrcinomas and head and neck carcinomas with the RARxcex1 specific or selective retinoid compounds. In accordance with the present invention the RARxcex1 selective compounds are also particularly advantageously used for treatment of proliferative vitreoretinopathy (PVR) and age related macular degeneration (AMD).
For the purposes of the present description a compound is considered RARxcex1 specific or selective if in a transactivation assay (described below) the compound transactivates the RARxcex1 receptors at a significantly lower concentration than the RARxcex2 and RARxcex93 receptors. Instead of measuring transactivation, measuring the binding of a compound respectively to the three RAR receptor subtypes is also feasible. Binding data expressed in Kd numbers obtained in a binding assay (described below) are also indicative of a compound""s ability to act specifically or selectively on RARxcex1 receptors in preference over RARxcex2 and RARxcex93 receptors. A compound is considered RARxcex1 specific or selective for the purposes of the present invention if the Kd number for its binding to RARxcex1 receptors is approximately 500 times smaller than the Kd for its affinity to RARxcex2 and RARxcex93 receptors.